Addition of Trastuzumab to Chemotherapy Produces 50% Increase in Survival in Patients Selected by FISH

October 1, 2001

Results from three retrospective studies demonstrated that fluorescence in situ hybridization (FISH) testing of tumor tissue for HER2 gene amplification is an effective method of selecting women with HER2-positive metastatic breast cancer who will

Results from three retrospectivestudies demonstrated that fluorescence in situ hybridization (FISH) testing oftumor tissue for HER2 gene amplification is an effective method of selectingwomen with HER2-positive metastatic breast cancer who will most likely respondto trastuzumab (Herceptin) therapy. Data from these studies were presented atthe 37th annual meeting of the American Society of Clinical Oncology (ASCO).

In the retrospective analysis of tumor tissue from women inthe phase III pivotal combination trial, those who were positive for HER2 geneamplification by FISH testing survived 50% longer—27 vs 18 months—whentreated with trastuzumab plus chemotherapy, as compared to those who receivedchemotherapy alone.

This result contrasts with the 24% increase in survival seenwhen the same tumors tested positive for HER2 protein overexpression byimmunohistochemistry testing.

Pivotal Trial

In the phase III pivotal first-line combination trial oftrastuzumab, lead author Dr. Robert Mass (a clinical scientist at Genentech) andcolleagues retrospectively tested and analyzed tumor tissue from 458 of 469patients. The goal of the trial was to determine how HER2 gene amplification,measured by FISH, compared with HER2 protein overexpression measured byimmunohistochemistry in identifying patients for trastuzumab therapy. HER2levels of 2+ and 3+ measured by immunohistochemistry were required forenrollment. (Overexpression is determined on a scale of 0 to 3+.)

Using the PathVysion FISH assay system, HER2 geneamplification was detected in 76% of the study population. Among those whotested positive by FISH, 89% were 3+ by immunohistochemistry and 31% were 2+. Inthe subgroup of FISH-positive patients, the addition of trastuzumab tochemotherapy resulted in an increase in the response rate to 54%, compared to31% for those receiving chemotherapy alone. No improvement in response rates wasseen in women whose tumors were negative for HER2 gene amplification by FISH(38% for trastuzumab with chemotherapy vs 37.5% for chemotherapy alone).

"These extensive retrospective analyses show us thatmeasuring gene amplification with FISH testing may provide more accurateinformation about potential tumor response rates and improvement in survivalwith Herceptin," said Dr. Mass.

FISH-Positive Patients Survive Longer

Two additional retrospective FISH analyses were presented byCharles Vogel, MD, lead investigator from the University of Miami Cancer Center,and colleagues. In an analysis of a study in which trastuzumab was administeredas a single agent to newly diagnosed HER2-positive metastatic breast cancerpatients, 82 of 111 participants found to be positive by immunohistochemistrywere also positive by FISH testing. The response rate for the subgroup found tobe positive by FISH was 34%, compared with 7% for the group deemed negative byFISH and 26% for those positive by immunohistochemistry. Time to diseaseprogression was 4.9 months for the FISH-positive group, 1.7 months for theFISH-negative group, and 3.5 months for those who were positive byimmunohistochemistry testing.

In an analysis of the single-agent pivotal trial oftrastuzumab as second- or third-line therapy after disease progression and oneor two chemotherapy regimens, 173 of 209 patients testing positive byimmunohistochemistry also tested positive by FISH. Response rates were 19% inthe FISH-positive group, 0% in the FISH-negative group, and 15% in the grouptesting positive by immunohistochemistry. Time to disease progression was 3.2months in the FISH-positive group, 1.9 months for FISH-negative patients,and 3.1 months for the immunohistochemistry-positive group.

Women in the FISH-positive group lived a median of 14.2months, compared with 8.8 months for women in the FISH-negative group—anincrease of 5.4 months or 61%. Overall survival for women in the trial whotested positive by immunohistochemistry was 12.8 months.

More Concentrated Dose of Trastuzumab More Effective

In a study presented by Dr. Karen Gelmon of British ColumbiaCancer Centre, Vancouver Centre, 25 women with HER2-positive metastatic breastcancer received a "triple dose" of trastuzumab (8 mg/kg as a loadingdose followed by 6 mg/kg) and paclitaxel (Taxol, 175 mg/m²) once every 3 weeks.After eight cycles of paclitaxel, patients continued to receive trastuzumabalone every 3 weeks. After two cycles, concentrations of trastuzumab weresimilar to those obtained in the once-weekly dosing studied in the pivotaltrial.

The every-3-week regimen did not appear to cause a clinicallysignificant increase in adverse events as compared to those seen with theonce-weekly dosing regimen. Adverse events included neutropenia, alopecia,fatigue, arthralgia, myalgia, and parasthesia, which are common side effects ofpaclitaxel therapy. One patient experienced grade III heart failure.

"Clinical studies have demonstrated that Herceptin given once weekly incombination with chemotherapy provides a significant survival benefit for womenwith HER2-positive metastatic disease," said Dr. Fyfe. "While thisstudy is preliminary, it suggests that administering a ‘triple dose’ ofHerceptin one-third as often, ie, every 3 weeks, may prove to be a moreconvenient schedule for women with HER2-positive metastatic breast cancer."